This proposal seeks a structured research training program, which will enable Chang-Gyu Hahn. M.D. Ph.D. to become an independent investigator as he demonstrates the utility of olfactory receptor neurons (ORNs) to examine the neurobiology underlying bipolar disorder. Career Goals and Objectives: With the career goat of being able to apply the most advanced molecular techniques to clinically relevant research paradigms through the ORN system, he proposes a career development plan focusing on following areas. 1) ionic imaging and the neurobiology of the human ORN system and 2) Single cell antisense RNA amplification technique. Career Development Activities: The candidate will receive specialized training in ionic imaging in human olfactory neurons (guided by Nancy Rawson, PILD, co-mentor) and in single cell molecular technique (supervised by James Eberwine, Ph.D., co-mentor). Dr. Karl Rickels will provide individual supervision for the treatment outcome study component of the specific aim 2. Dr. Robert H. Lenox will oversee the career development program through integrating formal courses, lab meetings and supervisions. Background: ORNs, the only CNS neurons that are obtainable through olfactory epithelial biopsy, provide a unique opportunity to investigate molecular events in neurons from living subjects. By obtaining ORNs during specific stages of the illness, in conjunction with a longitudinal follow-up of patients, pathophysiologic significance of molecular events in neurons can be linked to bipolar disorder. Hypothesis: Our preliminary data suggest that intracellular calcium responses to odbrants are altered in bipolar disorder. I) Intracellular calcium responses of ORNs to odorants are predominantly a decrease as a trait of bipolar disorder. 2) The decreased ICa responses in ORNs from bipolar patients are due to altered expression of the genes that are involved in calcium flux. 3) The percentage of ORNs that respond to odorant stimulation is overall decreased following lithium treatment. 4) ORNs in explant cultures from bipolar patients will show similar ICa responses as in vivo ORNs of patients. Specific Aims: 1) To characterize trait- and mood state- dependent alterations in ICa homeostasis and gene regulation in ORNs from bipolar patients. 2) To identify therapeutically relevant changes in ICa homeostasis following lithium treatment. 3) To characterize ORN cultures from bipolar patients using odorant induced ICa responses.